Exacerbation of type 1 diabetes in mice by bisphenol A and genistein

描述(申请人提供)：1型糖尿病(T1D)是一种器官特异性自身免疫性疾病，在过去的几十年里，全球每年以令人不安的约3%的速度增长，主要发生在较年轻的年龄段。同时也注意到接触内分泌干扰物(EDs)的增加，从而提出了可能的因果关系。由于其含量丰富，两种ED具有特别重要的意义：双酚A(BPA)，用于制造聚碳酸酯塑料以及水瓶、食品容器和牙齿填充物中的环氧树脂；以及染料木素(GEN)，一种普遍存在于大豆食品中的植物雌激素。对豆奶和双酚A联合暴露引起的异物代谢改变和协同作用的日益关注，包括在富含双酚A的婴儿奶瓶中，有必要研究Gen和双酚A在基于发育的出生后T1D中的相互作用。胸腺中枢耐受紊乱导致的T细胞活性异常在T1D流行中起着关键作用。同卵双胞胎中不一致的T1D发病率也表明表观遗传学在其表现中的作用。BPA和Gen都失调T细胞活性，并引起不适当的表观遗传修饰，这可能是T1D增加的原因之一。研究人员推测，T1D的恶化是因为围产期暴露于遗传易感的雌性非肥胖糖尿病小鼠和链脲佐菌素诱导的雌性糖尿病C57BL/6小鼠的胸腺免疫耐受受到破坏。研究人员认为，这种干扰是通过不适当的表观遗传修饰造成的，这种修饰使器官为随后的雌激素触发青春期期间的自身免疫做好了准备。上述中心假说将在下列两个目的的实验中得到解决：(1)确定围产期暴露于Gen和BPA后成年雌性小鼠T1D的加重，及其与胸腺基质微环境和白细胞介素17(IL)-17和Foxp3表达的关系；(2)检验产前暴露于Gen和BPA导致延髓胸腺上皮细胞T1D易感基因的组蛋白翻译后修饰区域的组蛋白翻译后修饰，以及Foxp3和IL-17基因座DNA甲基化和组蛋白乙酰化的变化。这些目标旨在有重点地扩展现有的BPA和GEN发育免疫毒性数据库，以集体需要的方式理解ED如何作为“健康和疾病的发育起源”化合物来增加晚年T1D的风险。表观遗传疗法，包括全球DNA去甲基化药物，已经转化为改善对癌症患者的护理，并表明拟议的研究对未来的T1D治疗具有潜在的临床重要性。这种识别：1)可能的基因靶点 在增加风险方面是重要的；2)生命中的脆弱时期；以及3)可能通过不同机制驱动导致T1D的免疫过程的环境因素，需要对干预研究做出知情决定，并产生潜在的生物标记物，用于后续的人类监测研究。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an organ-specific autoimmune disease that has been showing a disturbing global increase of approximately 3% per year, predominantly in the younger age groups, over the last decades. Parallel increased exposure to endocrine disruptors (EDs) has been noted, resulting in suggestions of possible causality. Two EDs of particular significance due to their abundance are bisphenol A (BPA), used in the construction of polycarbonate plastics as well as epoxy resins found in water bottles, food containers and dental fillings, and genistein (GEN), a prevalent phytoestrogen found in soy food. Growing concerns of altered xenobiotic metabolism and synergistic interaction from combined exposure to soymilk and BPA, including in BPA-laden baby bottles, has warranted the investigation of the interactions between GEN and BPA on development-based postnatal T1D. Dysregulated T cell activity resulting from disturbed thymic central tolerance plays a key role in the T1D epidemic. Discordant T1D incidence among monozygotic twins also suggested a role for epigenetics in its manifestation. BPA and GEN both dysregulate T cell activity and cause inappropriate epigenetic modifications, supporting a possible causal role in increased T1D. The investigators hypothesize that T1D is exacerbated because thymic immune tolerance is disrupted by perinatal BPA ¿ GEN exposure in genetically susceptible female non-obese diabetic mice and streptozotocin-induced female diabetic C57BL/6 mice. The investigators believe this disruption is through inappropriate epigenetic modifications, which prime the organ for subsequent estrogen-triggering of autoimmunity during peripuberty. The above central hypothesis will be addressed in the experiments of the following two Aims: (1) Determine the exacerbation of T1D in adult female mice following perinatal exposure to GEN and BPA, and its relationship to thymic stromal microenvironment and the expression of interleukin (IL)-17 and Foxp3; and (2) Test the hypothesis that prenatal exposure to GEN and BPA causes histone post-translational modifications at the promoter/enhancer regions of T1D susceptible genes in the medullary thymic epithelial cells, and changes of DNA methylation and histone acetylation in Foxp3 and IL-17 gene loci. These aims are designed as a focused expansion of the existing BPA and GEN developmental immunotoxicity database, in a manner collectively required to understand how EDs act as "developmental origins of health and disease" compounds to increase risk of later-life T1D. Epigenetic therapy including global DNA demethylating drugs, has translated into improved care for cancer patients, and suggests potential clinical importance of proposed studies for future T1D treatment. This identification of: 1) possible gene targets that are important in increasing risks; 2) vulnerable periods in life; and 3) environmental factors which through different mechanisms may be driving the immunological processes that lead to T1D is required to make informed decisions regarding intervention studies and produce potential biomarkers for use in subsequent human surveillance studies.